Many chronic and acute conditions are associated with perturbation of the inflammatory response. A large number of cytokines participate in this response, including, but not limited to, IL-1, IL-6, IL-8 and TNFα. Although these cytokines are expressed in a normal response to many physiological stimuli, excess, unregulated, or otherwise aberrant production of these cytokines can lead to inflammation and tissue damage. Diseases, for example, inflammatory and autoimmune diseases such as rheumatoid arthritis, can mediate morbidity though such aberrant production of cytokines (Keffer, J., et al, EMBO J., 13: 4025-4031, 1991, Feldmann, M., et al, Annu. Rev. Immunol., 14: 397-440, 1996 and Bingham, C. O., J. Rheumatol. Suppl., 65: 3-9, 2002). Currently there are several therapeutic agents that aim to reduce systemic levels of proinflammatory cytokines such as TNFα (Pugsley, M. K. Curr. Opin. Invest. Drugs, 2: 1725-1731, 2001 and Bondeson, J., and Maini, R. N., J. Clin. Pract., 55: 211-216, 2001; which are hereby incorporated by reference), and can thereby ameliorate disease. The current therapeutic agents act to reduce circulating levels of cytokines or neutralize activity of cytokines. The current therapeutic agents do not, however, directly block the intracellular proteins that regulate expression and secretion of proinflammatory cytokines. Moreover, the current therapeutic agents do not regulate the expression of other mediators of inflammation and tissue destruction.
The p38 MAP Kinase (also known as CSBP or SAPK, and hereinafter referred to as “p38”) signaling pathway has been reported to be responsible for the expression of pro-inflammatory cytokines that are elevated in many inflammatory and autoimmune diseases (see, e.g., Dong, C., et al., Annu. Rev. Immunol., 20: 55-72, 2002; which is hereby incorporated by reference). Inhibitors of any part of the p38 pathway or inhibitors of pathways that regulate the p38 pathway may be useful as therapeutics for diseases or conditions in which inflammation or autoimmune responses are involved. (Lee, J. C., et al, Immunopharm, 47: 185-201, 2000; which is hereby incorporated by reference). The p38 pathway has been shown to be activated by cellular stressors, such as osmotic shock, UV light, free radicals, bacterial toxins, viruses, cytokines, and chemokines, to name a few, and in response, mediates the expression of several cytokines including, but not limited to, IL-1, IL-6, IL-8 and TNFα (Ono, K. and Han, J., Cellular Signalling, 12: 1-13, 2000; which is hereby incorporated by reference).
The p38 pathway can be directly or indirectly activated by cell surface receptors, such as receptor tyrosine kinases, chemokine or G protein-coupled receptors, which have been activated by a specific ligand, e.g., cytokines, chemokines or lipopolysaccharide (LPS) binding to a cognate receptor. The p38 is activated by phosphorylation on residues threonine 180 and tyrosine 182. After activation, p38 can phosphorylate other intracellular proteins, including protein kinases, and can be translocated to the cell nucleus, where it can phosphorylate and activate transcription factors leading to the expression of pro-inflammatory cytokines and other proteins that contribute to the inflammatory response, cell adhesion, and proteolytic degradation. For example, in cells of myeloid lineage, such as macrophages and monocytes, both IL-1 and TNFα are transcribed in response to p38 activation. Subsequent translation and secretion of these and other cytokines initiates a local or systemic inflammatory response in adjacent tissue and through infiltration of leukocytes. While this response is a normal part of a physiological response to cellular stress, acute or chronic cellular stress can lead to excess, unregulated, prolonged, or otherwise aberrant expression of pro-inflammatory cytokines. This aberrant expression can lead to tissue damage, which often results in pain and debilitation. There are four known isoforms of p38 (p38α, p38β, p38δ and p38γ), each of which shows different expression levels, different tissue distribution, and different regulation patterns. This evidence supports the conclusion that p38 has a role in the etiology or sequelae of many diseases and physiological disturbances.
Many autoimmune diseases and diseases associated with chronic inflammation, as well as acute responses, have been linked to activation of p38, and activation of p38 in association with overexpression or dysregulation of other inflammatory cytokines. These diseases include, but are not limited to: rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptured, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; cancer; restenosis; silicosis; pulmonary sarcosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; and autoimmune diseases, such as Multiple Sclerosis, lupus and fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.
Studies have shown that reducing the activity of p38 blunts the inflammatory response and prevents or minimizes tissue damage (see, e.g., English, J. M. and Cobb, M. H., Trends in Pharmacol. Sci., 23: 40-45, 2002; and Dong, C., et al, Annu. Rev. Immunol., 20: 55-72, 2002; which are hereby incorporated by reference). Therefore, inhibitors of p38 activity that also inhibit excess or unregulated cytokine production and inhibitors that can inhibit more than a single pro-inflammatory cytokine may be useful as anti-inflammatory agents and therapeutics. The large number of diseases accompanied by p38-associated inflammatory responses indicates that there is a need for effective methods for treating p38- and cytokine-associated conditions. However, no approved drugs are available that are known to directly inhibit the p38 family of enzymes. Moreover, the approved drugs that act by reducing or neutralizing cytokine levels through binding to the cytokine are not orally bioavailable and must, therefore, be administered by techniques such as injection.
Accordingly, new compounds and methods for treating p38- and cytokine-associated conditions are needed.